Molecular basis of PD-1 blockade by dostarlimab, the FDA-approved antibody for cancer immunotherapy.
Biochem Biophys Res Commun
; 599: 31-37, 2022 04 09.
Article
en En
| MEDLINE
| ID: mdl-35168061
ABSTRACT
Targeting of programmed cell death 1 (PD-1) with monoclonal antibodies to block the interaction with its ligand PD-L1 has been successful in immunotherapy of multiple types of cancer, and their mechanism involves the restoration of the T-cell immune response. April 2021, the US FDA approved dostarlimab, a therapeutic antibody against PD-1, for the treatment of endometrial cancer. Here, we report the crystal structure of the extracellular domain of PD-1 in complex with the dostarlimab Fab at the resolution of 1.53 Å. Although the interaction between PD-1 and dostarlimab involves mainly the residues within the heavy chain of dostarlimab, the steric occlusion of PD-L1 binding is primarily contributed by the light chain. Dostarlimab induces conformational rearrangements of the BC, C'D and FG loops of PD-1 to achieve a high affinity. Significantly, the residue R86 within the C'D loop of PD-1 plays a critical role for dostarlimab binding by occupying the concave surface on the heavy chain via multiple interactions. This high-resolution structure can provide helpful information for designing improved anti-PD-1 biologics or effective combination strategies for cancer immunotherapy.
Palabras clave
Texto completo:
1
Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
Fragmentos Fab de Inmunoglobulinas
/
Anticuerpos Monoclonales Humanizados
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Receptor de Muerte Celular Programada 1
/
Inhibidores de Puntos de Control Inmunológico
Límite:
Humans
Idioma:
En
Revista:
Biochem Biophys Res Commun
Año:
2022
Tipo del documento:
Article